Despite the advent of many new antibiotics, osteomyelitis, in particular, chronic osteomyelitis, continues to represent a medical dilemma. Osteomyelitis is a bone infection caused by pyrogenic microorganisms, most commonly, Staphylococcus aureus. Infection may reach the bone directly, for example, through the blood stream or by direct extension from infections in adjacent structures. Very often, infection reaches the bone via compound (open) fracture.
Infection may be introduced to a compound fracture at the time of surgery, but more often, the infection is a result of contamination of the open fracture. It is estimated that 60-70% of open fractures are contaminated with various types of bacterial organisms prior to any surgical or antibiotic therapy. The growth of microorganisms in an open fracture environment is enhanced by the impaired vascularity, avascular bone fragments, and loss of skeletal stability. The majority of bacteria cultured from such wounds are either normal skin flora, for example, Staphylococcus aureus, Propionibacterium, or Cornybacterium, or environmental contaminants, for example, Clostridium, Pseudomonas, or Mycobacterium. In addition, nosocomial bacteria may colonize in the wound after hospital admission.
Infection may seriously complicate the healing process. Infections are the primary cause of non-union and bony instability following open fractures. Thus, the clinical objective in the treatment of open fractures is not only to stabilize osseous structures, but also to prevent soft tissue and bony infections.
There is a vast array of treatment options for stabilizing open fractures, including external and internal fixation methods. Although external fixation devices have, in theory, a lower potential for infection, statistically the rate of infection following external fixation ranges from 3.5-30%. This rate is comparable to the incidence of infection using internal fixation techniques and antibiotics. In addition, external fixation procedures are fraught with other potential complications. For example, long periods of external pin fixation often result in pin loosening, pin tract infections, and increased incidence of malunion and non-union.
Alternatively, compound fractures may be fixed internally, for example, with plates or intramedullary rods. Such procedures were initially unpopular despite the excellent skeletal fixation because of the increased infection potential with the introduction of a metallic foreign body into the human body. However, stabilization of the open fracture site is critical for local wound healing and the resolution of a potentially infected wound. The stability provided by internal fixation devices far outweighs the disadvantages of the potentially infected foci. As a result, use of internal fixation devices is increasing.
Empiric utilization of antibiotic therapy has been shown to be extremely important in reducing the incidence of infection. The prognosis of patients undergoing antimicrobial therapy is determined by the bactericidal level of antibiotics at the locale of the infected foci. A persistent problem with treating any localized infection by systemic administration of antibiotics is that the relationship between the assayed serum antibiotic concentration and the level present at the infected foci is inconsistent, especially when the foci is traumatized tissue. Antibiotic concentrations are often subtherapeutic due to impaired vascularity at the fracture site, devitalized bony fragments, and/or associated systemic complications. The situation is compounded by the anaerobic conditions of the infected foci that further decrease the effectiveness of antibiotics. Consequently, high doses of parenteral antibiotics must often be used to achieve adequate local concentrations. The high doses are not only costly, but also increase the incidence of systemic side effects, for example, ototoxicity or nephrotoxicity.
The treatment of osteomyelitis due to compound fracture or other cause, often fails due to the inability to achieve adequate antibiotic levels at the infected foci. As a result, the patient may experience many episodes of recurrence and sepsis.
As can be seen from the foregoing, there is a need for materials and methods which enable clinicians to achieve a therapeutically effective concentration of antibiotic at the infected foci. Local therapy methods include local injection, closed irrigation and suction, implantable antibiotic pumps and antibiotic impregnated beads. Tsukayama et al., Orthopedics, 11:1285 (Sept. 1988) disclose an example of a non-degradable implant using polymethylmethacrylate (PMMA) beads containing an antibiotic to achieve local concentrations of particular antibiotics at the site of infection. Three of the antibiotics tested, vancomycin, teicoplanin and ciprofloxacin, were found to be active against staphylococci under anaerobic conditions. However, a significant problem with any non-degradable implant is that once the implant is spent, it must be removed.
Accordingly, an implantable biodegradable delivery system is preferred because there is no need for subsequent procedures to remove the implant system. Further, such systems are able to localize the concentration of antibiotic to the area of infection, for example, the bone, while avoiding problems associated with administering high doses of antibiotic systemically.
A few biodegradable drug delivery systems have recently been suggested for the treatment of chronic osteomyelitis. Lin et al., "Evaluation of a biodegradable drug delivery system for chronic osteomyelitis," 38th Annual Meeting, ORS, Washington D.C., Feb. 17-20, 1992; Robinson et al., "Preparation and degradation of a biodegradable gentamycin delivery system for the treatment of osteomyelitis," 38th Annual Meeting, ORS, Washington D.C., Feb. 17-20, 1992; Garvin, et al., "Treatment of Canine Osteomyelitis with a Biodegradable Antibiotic Implant," 38th Annual Meeting, ORS, Washington D.C., Feb. 17-20, 1992; Wei et al., "A bioabsorbable delivery system for antibiotic treatment of osteomyelitis," J. Bone Joint Surg. 73B:246-52 (1991). However, such delivery systems have not been demonstrated to be appropriate for use with antibiotics demonstrated to be effective under anaerobic conditions in bones in pathological states.
For example, Wei et al., disclose that a biodegradable carrier of D,L-lactic acid oligomer having an average molecular weight of 9000 can be combined in its powder form with the antibiotic dideoxykanamycin B to form a small rod (approximately 3 mm in diameter by 10 mm in length) to be implanted into a bone via a burr hole made in the bone for the purpose of implanting the rod therein. J. Bone Joint Surg. 73(B):246 (Mar. 1991). However, testing was not conducted on bones in various pathological states. Further, the efficacy of this system for use with any of the antibiotics shown by Tsukayama et al., to be effective under anaerobic conditions similar to those found in infected bone has not been demonstrated. To the contrary, Weston et. al. (37th Annual Meeting, Orthopaedic Research Soc'y, Mar. 4-7, 1991, Anaheim, CA), disclose that ciprofloxacin, an antibiotic demonstrated to be effective under anaerobic conditions, is incompletely released from an implant using poly(L-lactide) as a carrier. Thus, the references suggest that a poly(1-lactide)-ciprofloxacin implant would not be effective for the treatment of osteomyelitis.
There is a heretofore unmet need for biodegradable drug delivery systems that are appropriate for use with compromised bone, for example, fractured bone. Such delivery systems preferably combine an antibiotic efficient under anaerobic conditions, for example an aminoglycoside antibiotic or quinolone, especially ciprofloxacin, with a biodegradable carrier to form an intramedullary rod for use in the reduction of open fractures as well as the prevention and/or treatment of infection.